A limited but important degree of neurological recovery occurs after Spinal Cord Injury (SCI). Anatomical plasticity of synaptic connections at multiple levels of the neuraxis from the cerebral cortex to the caudal spinal cord is likely to contribute to this functional recovery. To exploit and optimize plasticity-based recovery of function for SCI, it is essential to define its cellular nature and extent. Anatomical plasticity wthin the cerebral cortex has been examined to a very limited extent after SCI, even though it is a likely site for plasticity. Furthermore, the stability of individual synapses has never been monitored in vivo after SCI. Using time-lapse in vivo two-photon microscopy we will image synaptic connections in the cerebral cortex after SCI to determine the extent of rearrangement at the synaptic level. Importantly, the role of training, CSPG and NgR1 in modulating recovery will be linked to cortical synapse dynamics. Using region-specific conditional gene deletion and optogenetic mapping, we will determine the functional significance of anatomical plasticity in cortical synapses during SCI recovery. The findings have the potential to establish cortically directed therapeutic interventions as cellular targets for SCI rehabilitation. PUBLIC HEALTH RELEVANCE: After Spinal Cord Injury there is partial recovery of function. Enhancing endogenous mechanisms of partial recovery holds great therapeutic promise. Unfortunately, the cellular and molecular basis of natural recovery is not clear. A likely, but undocumented, mechanism is the rearrangement of neural connectivity via plasticity of synapses in cerebral cortex and other sites. We will test the hypothesis that those molecular and rehabilitative interventions that improve behavioral recovery do so by enhancing synaptic rearrangement in the cerebral cortex. The findings have the potential to establish cortically directed therapeutic interventions as key target for SCI recovery.